Acute lymphoblastic leukemia (ALL) is the most common form of childhood malignancy. Chemotherapy can cure 80% of these children, but unfortunately many still relapse or develop resistant disease. Those that survive often suffer from adverse toxicity. This proposal investigates the mechanisms by which monoclonal antibodies (Mabs) induce apoptosis alone or in combination with chemotherapy in childhood B-lineage ALL. B-lineage lymphoblasts obtained from patients with leukemia undergo spontaneous and chemotherapy induced apoptosis. Like their normal counterparts (i.e., lymphocytes), they are "primed" to undergo apoptosis. Mabs have been shown to enhance the effect of chemotherapy in both laboratory and clinical settings. Mabs are capable of signaling various intracellular events and modulating the expression of genes involved in apoptosis. There exists only limited information on how Mabs and chemotherapy work together to enhance the cytotoxic effect upon leukemia. There is currently a lack of understanding of the mechanisms involved when Mabs are used to target B-lineage ALL as individual agents or in combination with chemotherapy. Our hypothesis is that the leukemia cell can undergo apoptosis in response to Mabs, the response can be enhanced with chemotherapy; and that key apoptotic related genes will be up-regulated or down-regulated, thereby elucidating the pathway leading to cell death. Knowledge of this pathway may allow for the selection of agents capable of enhancing the degree of apoptosis. We plan to correlate the cellular response to a specific profile of mRNA expression. These studies may identify genes that are important in the initiation of apoptosis that have not previously been linked with this phenomenon. These studies will also allow us to determine if the degree of apoptosis demonstrated in vitro correlate with drug sensitivity in vivo. We will determine if apoptosis and gene profile analysis can predict the most effective agents in treating leukemia in a SCID/human ALL mouse model. We will then develop new treatment regimens for children with multiply relapsed leukemia based on this information. [unreadable] [unreadable]